Abstract It is well established that helminth infections impact human immune responses, but the mechanisms are incompletely understood. We hypothesize that the impact of helminths could be indirectly mediated by alterations to the gut microbiota during infection. Both helminths and the gut microbiota can exert powerful systemic immunoregulatory effects. Changes to the prevalence of helminth infections and the microbiota may be environmental factors contributing towards the ?hygiene hypothesis? and the rising incidence of autoimmune diseases in developed nations. Dysbiosis (dysregulation of microbial communities) is a common feature of many human diseases, especially those with an inflammatory component. We have studied the effects of helminth colonization on the microbiota of indigenous Malaysians, called the ?Orang Asli?. Our preliminary results have identified an antagonistic relationship between microbial communities dominated by either Bacteroidales or Clostridiales communities. The expansion of Clostridiales over Bacteroidales communities can be driven by type 2 cytokines (IL-4 and IL-13), which promote increased mucus production by goblet cells. Mucus can directly promote the growth of human Clostridial strains. Using mouse models, we could demonstrate that a cocktail of Clostridial strains could directly inhibit a Bacteroides dominated community, even in the absence of helminth infections. We hypothesize that the expansion of Clostridiales communities by helminth colonization promotes anti-inflammatory responses within the host; and that Clostridiales strains from the Orang Asli are more potent at immune-regulation than existing strains. The effects of diet and nutrient intake and the interactions between helminth colonization and bacterial networks need to be established. To test these ideas, we will assess alterations to the gut microbiota of Orang Asli populations undergoing public health deworming programs. Along with dietary surveys, the proposed field studies will provide longitudinal analyses of helminth-colonized individuals to establish cause and effect relationships of helminths on the gut microbiota. Finally, we will isolate bacterial strains from the Orang Asli and determine whether they replicate the anti-inflammatory effects of helminths in mice. Understanding physiological processes involved in the intersection of infection, nutrition, microbiota and inflammation, could promote biomarker discovery and identify novel interventional strategies towards improving global health. Our study builds upon existing collaborations between Dr. Loke (NYU), Dr. Lim (University of Malaya), Dr. Cadwell (NYU) and Dr. Bonneau (NYU), with expertise in parasitology, microbiota studies, microbiology and immunology, epidemiology and field studies, computational biology and biostatistics. Accomplishment of the above goals will have important implications to individuals living in both developing countries as well as developed countries.